The role of HGFL in the sickle cell disease nephropathy

HGFL 在镰状细胞病肾病中的作用

基本信息

批准号：
10021022
负责人：
MARINA A JEREBTSOVA
金额：
$ 38.63万
依托单位：
HOWARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-19 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10021022
关键词：
Affect African Anatomy Apoptosis Basic Science Biological Biological Assay Biological Markers Blood Vessels Caring Case-Control Studies Cell Line Cells Cessation of life Chicago Chronic Kidney Failure Cleaved cell Complex Core Facility Detection Development Disease Disease Progression Early Diagnosis Endocytosis Endothelial Cells Endothelium Enzyme-Linked Immunosorbent Assay Epithelial Cells Erythrocytes Event Experimental Models Funding General Population Genes Globin Glomerular Filtration Rate Goals HGF gene Heme Hemoglobin Hemolysis Hereditary Disease Human Illinois Infiltration Injury Injury to Kidney Investigation Iron Kidney Kidney Diseases Knowledge Liver Macrophage Activation Mass Spectrum Analysis Membrane Mesylates Methods Monitor Mus Mutation Nucleotides Onset of illness Oxygen Pathway interactions Patients Peptide Hydrolases Phosphotransferases Prognostic Marker Protease Inhibitor Protocols documentation Public Health Reaction Receptor Activation Receptor Protein-Tyrosine Kinases Renal Tissue Renal glomerular disease Research Role ST14 gene Sampling Sickle Cell Sickle Cell Anemia Testing Therapeutic Intervention Tubular formation Universities Vascular Diseases activation product beta Globin cell injury cohort comorbidity design diagnosis standard disease diagnosis early detection biomarkers effective therapy faculty research glomerular endothelium high risk improved inhibitor/antagonist laboratory development macrophage macrophage stimulating protein monocyte mortality mouse model new therapeutic target novel novel diagnostics novel therapeutic intervention novel therapeutics podocyte polymerization prevent pro-hepatocyte growth factor receptor receptor expression renal damage repository research clinical testing tool tool development translational research program urinary

Affect African Anatomy Apoptosis Basic Science Biological Biological Assay Biological Markers Blood Vessels Caring Case-Control Studies Cell Line Cells Cessation of life Chicago Chronic Kidney Failure Cleaved cell Complex Core Facility Detection Development Disease Disease Progression Early Diagnosis Endocytosis Endothelial Cells Endothelium Enzyme-Linked Immunosorbent Assay Epithelial Cells Erythrocytes Event Experimental Models Funding General Population Genes Globin Glomerular Filtration Rate Goals HGF gene Heme Hemoglobin Hemolysis Hereditary Disease Human Illinois Infiltration Injury Injury to Kidney Investigation Iron Kidney Kidney Diseases Knowledge Liver Macrophage Activation Mass Spectrum Analysis Membrane Mesylates Methods Monitor Mus Mutation Nucleotides Onset of illness Oxygen Pathway interactions Patients Peptide Hydrolases Phosphotransferases Prognostic Marker Protease Inhibitor Protocols documentation Public Health Reaction Receptor Activation Receptor Protein-Tyrosine Kinases Renal Tissue Renal glomerular disease Research Role ST14 gene Sampling Sickle Cell Sickle Cell Anemia Testing Therapeutic Intervention Tubular formation Universities Vascular Diseases activation product beta Globin cell injury cohort comorbidity design diagnosis standard disease diagnosis early detection biomarkers effective therapy faculty research glomerular endothelium high risk improved inhibitor/antagonist laboratory development macrophage macrophage stimulating protein monocyte mortality mouse model new therapeutic target novel novel diagnostics novel therapeutic intervention novel therapeutics podocyte polymerization prevent pro-hepatocyte growth factor receptor receptor expression renal damage repository research clinical testing tool tool development translational research program urinary

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项目摘要

Sickle cell disease (SCD) is caused by a single nucleotide mutation in the β-globin gene resulting in the polymerization of hemoglobin (HbS) in red blood cells (RBCs) under low oxygen conditions leading to hemolysis and vaso-occlusion. SCD is the most common hereditary disorder which affects approximately 100,000 people in the USA, primarily of African descent. Renal complications are the most common complications in SCD patients. They range from various tubular and glomerular functional abnormalities to gross anatomic alterations of the kidney. Overall, SCD patients have an approximately three-fold higher risk to develop chronic kidney disease (CKD) than the general population. More than 50% of SCD patients develop CKD in association with comorbidities and early mortality. However, the current standards of diagnosis and care can only delay progression of this disease. This is due to a lack of effective therapies and an absence of reliable assays for diagnosis of the early disease, before renal damage is severe or irreversible. New diagnostic and therapeutic tools are urgently needed. Development of these tools requires an improved understanding of the disease mechanism and identification of new biomarkers of disease onset and progression. The majority of renal complications of SCD result from functional vasculopathy and endothelial injury. In contrast, the key event in the development of glomerular complications leading to CKD is podocyte injury. This highlights a major gap in our knowledge of the mechanism of glomerular disease development in SCD. This proposal lays out a sophisticated approach to validate the role of hepatocyte growth factor like (HGFL) protein in the development of CKD in SCD. We hypothesize that RBC hemolysis products activate protease in infiltrated renal macrophages inducing a cascade of circulating HGFL activation and glomerular endothelial and epithelial cell injury. In Aim 1, macrophage activation by the products of sickle RBC hemolysis and its role in the development of glomerular injury will be studied. In Aim 2, the role of HGFL and its receptor, RON, in the induction of glomerular podocytes injury will be evaluated. In Aim 3, target-specific quantitative assays, e.g. ELISA and single reaction monitoring mass-spectrometry will be used to validate correlation of urinary HGFL levels with estimated glomerular filtration rates (eGFR) in case-control study using Howard University Center for Sickle Cell Disease repository samples. This proposal is designed to evaluate the role of HGFL in the development of glomerular injury in SCD and validate HGFL as a novel diagnostic tool for hyperfiltration detection. A faculty research enhancement plan includes a strategy that will lead to developing an independently-funded basic and translational research program in SCD renal disease.

镰状细胞疾病（SCD）是由β-珠蛋白基因中的单个核苷酸突变引起的，导致在低氧气条件下，红细胞（RBC）中血红蛋白（HBS）聚合导致溶血和血管封闭。 SCD是最常见的遗传疾病，影响美国有100,000人，主要是非洲血统。肾脏并发症是最常见的 SCD患者的并发症。它们的范围从各种管状和肾小球功能异常到肾脏的解剖学变化。总体而言，SCD患者的风险高约三倍比普通人群发展慢性肾脏疾病（CKD）。超过50％的SCD患者发展 CKD与合并症和早期死亡率相关。但是，诊断的当前标准和护理只会延迟这种疾病的进展。这是由于缺乏有效的疗法和缺乏在肾脏损伤之前，可靠的诊断早期疾病的疾病是严重或不可逆的。新的迫切需要诊断和治疗工具。这些工具的开发需要改进了解疾病机制和鉴定疾病发作的新生物标志物和进展。 SCD的大多数肾脏并发症是由功能性血管病和内皮引起的相反，导致CKD的肾小球并发症发展的关键事件是足细胞受伤。这凸显了我们对肾小球疾病发展机制的了解 scd。该提议提出了一种复杂的方法来验证肝细胞生长因素的作用（HGFL）在SCD中CKD开发中的蛋白质。我们假设RBC溶血产物激活浸润的肾脏巨噬细胞中的蛋白酶，诱导一系列循环HGFL激活和肾小球内皮和上皮细胞损伤。在AIM 1中，镰刀RBC溶血的产物激活巨噬细胞它在肾小球损伤发展中的作用将研究。在AIM 2中，HGFL及其接收器的角色，罗恩（Ron）将评估肾小球足细胞损伤的诱导。在AIM 3中，目标特异性定量测定，例如ELISA和单一反应监测质谱法将用于验证相关性在病例对照研究中，使用霍华德进行估计的肾小球过滤率（EGFR）的尿HGFL水平（EGFR）大学镰状细胞疾病存储库样品中心。该建议旨在评估 HGFL在SCD中肾小球损伤发展并验证HGFL作为新型诊断工具中的HGFL 过滤检测。教师研究增强计划包括一项策略，该策略将导致发展 SCD肾脏疾病的独立基本和翻译的研究计划。